Fever work up
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I now have a very comprehensive set of information from Harrison's 22E and Frameworks for Internal Medicine. Let me compile the full fever workup answer.
Fever Work-Up
Definition
Fever = temperature ≥38.3°C (≥101°F). Fever of Unknown Origin (FUO) is defined as:
- Fever ≥38.3°C on at least two occasions
- Illness duration of ≥3 weeks
- No known immunocompromised state
- No diagnosis despite basic workup
Most febrile illnesses either resolve spontaneously or develop localizing features before meeting FUO criteria. True FUO requires intensive evaluation.
The Four Categories of FUO
| Category | Proportion (Western Europe) | Key Entities |
|---|---|---|
| Infectious | ~15.5% | Occult abscess, TB, endocarditis, osteomyelitis, viral, zoonoses |
| Non-infectious inflammatory (NIID) | ~25% | Adult Still's, GCA, PMR, SLE, sarcoidosis, IBD, autoinflammatory |
| Malignant | ~11% | Lymphoma, leukemia, MDS, RCC, solid tumors |
| Miscellaneous/Other | ~7.5% | Drug fever, DRESS, familial Mediterranean fever, Behçet's |
| No diagnosis | ~39.5% | Many resolve spontaneously |
History & Physical Examination
History - key elements:
- Fever pattern (quotidian = Still's; hectic = abscess/lymphoma; tertian/quartan = malaria)
- Duration, associated symptoms (weight loss, night sweats, arthralgias, rash)
- Travel history (malaria, leishmaniasis, histoplasmosis, coccidiomycosis)
- Animal exposure (Q fever/Coxiella = cattle/sheep; cat scratch = Bartonella)
- Occupational exposure, sick contacts
- Prior malignancy, cardiac valvular disease, prior surgeries, prosthetics
- Medications - virtually ALL drugs can cause fever, even after long-term use
- Family history (FMF in Mediterranean ethnicity - Arab, Armenian, Turkish, North African, Jewish)
- Sexual history, IV drug use (HIV, endocarditis)
Exam clues:
- Temporal artery tenderness/thickening → GCA
- New cardiac murmur → endocarditis
- Lymphadenopathy → lymphoma, infectious mononucleosis, TB
- Hepatosplenomegaly → lymphoma, chronic infection, leishmaniasis
- Salmon-colored evanescent rash (appears with fever, disappears when afebrile) → Adult-onset Still's disease
- Skin/nail changes → drug reaction, vasculitis
- Fundoscopic exam → uveitis (sarcoidosis, TB, Behçet's)
Initial Laboratory Work-Up (Tier 1)
| Test | What It Detects |
|---|---|
| CBC with differential | Leukocytosis (infection), leukopenia (SLE, viral), anemia, atypical lymphocytes, blast cells |
| CMP (BMP + LFTs) | Hepatic involvement, renal disease |
| ESR + CRP | Systemic inflammation (very elevated in GCA, Still's) |
| Urinalysis + urine culture | UTI, renal abscess, RCC (hematuria) |
| Blood cultures x3 | Bacteremia, endocarditis (collect before antibiotics) |
| LDH, uric acid | Lymphoma, hemolysis |
| ANA, anti-dsDNA, complement | SLE screen |
| Serum ferritin | Markedly elevated (often >2000 ng/mL) in Adult Still's disease |
| TSH | Thyroid disease as a cause of fever |
| HIV serology/Ag | Acute or chronic HIV |
| PPD/IGRA (Quantiferon) | TB exposure/latent TB |
| Peripheral blood smear | Malaria (if travel history), hemolysis |
| Rheumatoid factor + anti-CCP | RA |
| Chest X-ray | TB, hilar adenopathy (sarcoidosis, lymphoma), malignancy |
Imaging Work-Up (Tier 2)
| Study | Indication/Yield |
|---|---|
| CT abdomen/pelvis with contrast | First-line imaging; detects intra-abdominal abscess (most common infectious FUO cause), occult malignancy. High yield - should be one of the FIRST studies in FUO |
| CT chest | Hilar/mediastinal adenopathy, pulmonary infiltrates, TB pattern |
| Echocardiogram (TTE/TEE) | Infective endocarditis - TEE more sensitive than TTE |
| FDG-PET/CT | Highly valuable in FUO - detects occult infection, malignancy, vasculitis. Often used when initial workup is unrevealing |
| MRI spine | Vertebral osteomyelitis (most common site of osteomyelitis in FUO) |
| Labeled leukocyte scintigraphy | Occult infection, IBD activity |
Specific Infectious Causes and Their Work-Up
| Pathogen | Clue | Investigation |
|---|---|---|
| Intra-abdominal abscess | History of biliary disease, diverticulitis, Crohn's, appendicitis; abdominal tenderness (may be absent in elderly) | CT abdomen |
| TB (extrapulmonary/miliary) | Immunocompromised, endemic region, no CXR findings | IGRA/TST, sputum AFB smear/culture/PCR, BAL, bone marrow biopsy |
| Endocarditis | Valvular disease, prosthetic valve, IVDU, new murmur | 3 sets blood cultures (before abx), TEE, serology for atypical organisms (Bartonella, Coxiella, Brucella) |
| Vertebral osteomyelitis | Back pain, prior bacteremia | MRI spine, bone culture |
| EBV/CMV | Young patient, pharyngitis, splenomegaly, atypical lymphocytes | EBV heterophile Ab/VCA IgM, CMV IgM/PCR |
| Q fever (C. burnetii) | Rural area, animal exposure, valvular disease | IFA serology |
| Bartonella (cat scratch) | Pet cat, regional lymphadenopathy | Serology, PCR |
| Brucella | Livestock/dairy exposure | Blood cultures (prolonged incubation), serology |
| Whipple's (T. whipplei) | GI symptoms, neurologic, joint involvement | PCR on stool and blood |
| Malaria | Travel to endemic region | Thick/thin blood smears x3, malaria RDT, PCR |
| Leishmaniasis | Travel to Mediterranean, South Asia, South America | Serology, bone marrow aspirate |
| Histoplasma/Coccidioides | Travel to Ohio/Mississippi Valley or American Southwest | Urine/serum antigen, serology, BAL culture |
Non-infectious Inflammatory Causes and Their Work-Up
| Disease | Key Clue | Investigation |
|---|---|---|
| Adult-onset Still's disease (AOSD) | Quotidian high fever, salmon rash, pharyngitis, arthralgias, ferritin >2000 | Clinical dx; ferritin, leukocytosis, LFTs, CRP |
| Giant cell arteritis (GCA) | Age >50, headache, jaw claudication, elevated ESR; accounts for ~20% FUO in elderly | ESR, CRP, temporal artery biopsy, vascular US/PET |
| Polymyalgia rheumatica (PMR) | Shoulder/hip girdle pain & stiffness, associated with GCA | Clinical diagnosis; ESR, CRP; dramatic response to steroids |
| SLE | Young woman, leukopenia, rash, serositis | ANA, anti-dsDNA, complement (C3/C4) |
| Sarcoidosis | Bilateral hilar adenopathy, skin, eye, liver involvement | Chest CT, ACE level, tissue biopsy showing non-caseating granulomas |
| IBD | GI symptoms, rarely presents as FUO (mainly UC) | Colonoscopy, PET/labeled leukocyte scan |
| FMF (Familial Mediterranean fever) | Mediterranean ancestry, periodic attacks, serositis, first attack <20 years, attacks last 1-4 days | Clinical; MEFV gene mutation testing; response to colchicine |
| VEXAS syndrome | Middle-aged/elderly males, skin lesions, chondritis, lung disease, MDS | Bone marrow biopsy (vacuoles in myeloid precursors), UBA1 somatic mutation |
Malignant Causes and Their Work-Up
- Lymphoma (most common malignant FUO) - lymphadenopathy may follow fever onset; CXR, CT, PET, LN biopsy
- Leukemia - CBC, peripheral smear, bone marrow biopsy
- MDS - macrocytosis; bone marrow biopsy
- Renal cell carcinoma (RCC) - hematuria, polycythemia, flank mass; CT abdomen
- Hepatocellular carcinoma - cirrhosis background; AFP, liver US/CT
- Colon cancer (associated with S. gallolyticus endocarditis) - colonoscopy
In patients with known malignancy presenting with FUO: infection is the most common cause, not the tumor itself.
Drug Fever
Virtually ALL drugs can cause fever, even after years of use. Classic culprits include beta-lactam antibiotics, sulfonamides, phenytoin, allopurinol, hydralazine, and procainamide. DRESS (drug-induced hypersensitivity syndrome with eosinophilia) is a severe form. Diagnosis is largely one of exclusion - fever resolves within days of stopping the offending agent.
Advanced/Invasive Work-Up (Tier 3 - if Tier 1/2 unrevealing)
| Procedure | Indication |
|---|---|
| Bone marrow biopsy | Suspected lymphoma, leukemia, miliary TB, MDS, histoplasmosis, leishmaniasis |
| Liver biopsy | Granulomatous hepatitis, miliary TB, hepatic TB, lymphoma |
| Lymph node biopsy | Persistent lymphadenopathy - lymphoma, sarcoid, TB |
| Temporal artery biopsy | Suspected GCA |
| Lumbar puncture | CNS involvement; T. whipplei PCR if indicated |
| Next-generation sequencing (NGS/mNGS) | Culture-negative endocarditis, unidentified pathogens; exact role still being defined |
Empirical Treatment - When and What
Empirical therapy should generally be avoided as it can mask diagnoses. Exceptions:
- Hemodynamic instability or neutropenia → empirical broad-spectrum antibiotics
- Positive IGRA/TST + suggestive picture → anti-TB therapy (only after cultures/PCR obtained)
- Strong suspicion of GCA (vision threatened) → empirical glucocorticoids
- FMF suspected → colchicine trial (diagnostic and therapeutic)
- Still's disease suspected → NSAIDs (dramatic response in some); glucocorticoids second-line
- Autoinflammatory syndromes → IL-1 inhibitors (anakinra) highly effective for FMF, Still's, CAPS, TRAPS, MKD
Glucocorticoids should NOT be used empirically until infection and lymphoma are sufficiently excluded - they can mask fever while allowing spread of both.
Prognosis
When no diagnosis is reached after extensive evaluation, the majority of FUO cases resolve spontaneously and the long-term prognosis is generally favorable. Mortality risk is highest during the early diagnostic phase.
Sources: Harrison's Principles of Internal Medicine 22E (2025), Frameworks for Internal Medicine, Goldman-Cecil Medicine
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